SPECIFIC AIMS We proposed that changes in the energetic cost of walking is implicated in the causal pathway that leads to progressive functional decline and disability in older persons. We have previosly proposed that change in walking speed in older individuals is induce by the feeling of fatigue that occur at low level of excercise effort. Slowing down speed is a compensatory strategy to reduce the level of effort and avoid fatigue. We also hypothesize that fatigue occur when the instantaneous metabolic rate approaches the maximum metabolic rate allowed for a certain individual, which is ususally expressed and MVO2 max during a treadmill exercise. The higher the metabolic rate for a certain level of effort, the more likely is that that individual is close to the level of maximum energy availability. However, metabolic rate can have two different sources: a. Resting metabolic rate, which is the energy required to maintain life in a homeostatic equilibrium at rest and in euthermic conditions;b. Movement efficiency, which is the amount of energy (MVO2) required to perform one unit of energy. There is emerging evidence that resting metabolic rate declines with age in healthy individuals, but does not decline, or perhaps even increases, in older individuals who are sick or frail. Analogously, movement efficiency tends to decline with age, a change that is explained only in part by changes in body composition. Thus, older persons require more energy, or higher metabolic rate, to perform the same activity than younger individuals. In parallel, it is well know that aerobic capacity declines with age. This has been demostrated longitudinally in the BLSA and is not confirmed in many other studies. Thus there are multiple energetic reasons why older person who perfome a certain activity tend to perceive more fatigue than younger ones. In addition, the perception of fatigue, given the same ratio between energy availability/energy utilization is probably modulated by several factors including inflammation, depression and others related to "sickness behaviour". The aim of this project is to measure these energetic variable in the BLSA, to unravel the mechanism of the prognostic value of walking speed in older individuals, which has been demonstrated in many epidemiological studies. In particular, we hypothesize that low fatigue threshold in frail older eprsons is due to: - increased RMR due to high cost of homeostasis and dysregulation or malfunction of the homeostatic network (due to both acute and chronic diseases processes); - increased energetic cost of mobility due to increased biomechanical inefficiency and decline in the anatomical integrity and harmonic function of the "human ambulatory machine"; - compromised energy availability , due to specific pathological processes, CHF for instance, and/or inefficient transport of energy to the required sites, mainly due to reduced homeostatic ability. RESEARCH PLAN To test the hypothesis high energetic cost of walking, increased RMR and and development of fatigue at low levels of activity are key predictor of disability, we propose to explore the relationship between RMR, the energetic and mechanical aspects of walking (gait lab) and the threshold for the development of fatigue in the participants of the BLSA.. Outcomes of the study Primary outcome: to evaluate whether higher RMR, high energetic cost of walking, maximum oxigen consumption during peack exercise and a dysregulation of the energy homeostatic network (level of inflammatory markers and hormones) are independent predictors of energetic threshold for the development of subjective fatigue. Secondary outcome: to verify whether information on RMR, energetic cost of walking, maximum oxigen consumption during peack exercise and dysregulation of the energy homeostatic network provide information on fitness and fatigability independent of the measure of fitness provided by a standard treadmill tests. Study population Participants will consist of all BLSA participants. No exclusion criteria are established a priori. We seek to routinely measure oxygen consumption at rest, during normal walking and prolonged walking (400 m). Since portable equipment is already used during the normal testing, no additional time will be required to the BLSA scheduling of the participants. Threshold of fatigue will be estimated using Borg Scale. Each participant will be administered the Borg Scale at predetermined intervals during the physical task. Implementation of the BLSA to test the energetic pathway of disability We have introduced in BLSA measures of objective and subjective fatigue using the Borg Scale and the RQ ratio, respectively. This measurements will be performed at regular intervals during the tasks evaluating physical performance. In addition, we will be measuring metabolic rate using a portable equipment in different conditions, including rest, pre-exercise, customary walking, treadmill at low load and maximum load. Part of the study is to verify the hypothesis that change change in the circulating level of hormones, inflammatory markers, markers of oxidative stress and autonomic function modulates the relationship between workload, energy consumption and the development of fatigue. Finally, we have introduced in the BLSA measures of metabolic consumption during daily activity, asking participants to wear an accelerometer combined with a heart rate recored for seven days after leaving the clinic. Using individuals claibration equations elaborated during their stay in the BLSA, we plan to estimate their usual daily activity and to correlate it with our measures of efficiency and energetics.